TW389764B - 6-(2-imidazolinylamino) quinoline compounds useful as alpha-2 adrenoceptor agonists - Google Patents

Description

A7 _B7 _-V. Description of the invention (1) Fangheng Festival The present invention is directed to a specific substituted 6- (2-oxazolinylamino) denoline compound. These compounds have now been found to be effective in promoting the failure of the _2 »epiphyseal receptors. • K can be used to treat one or more respiratory diseases, especially nasal congestion; eye diseases, especially blue eyes; and iliac bowel disease, Especially diarrhea. Tocopherol can be affected by fl · stimulants and antagonists-as well as compounds that are related to the structure of the compounds of the present invention-Information has been shown in the following documents: 'Tinenans, PBMWH, AT Chiu & HJHC Thoolen,. &Quot; 12.1 a -Adrenergic Receptors ",

(Printed by the Central Government Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives I * ^ 4? Please read the precautions on the back before filling out this page)

Comprehensive Medicinal Chemistry. Vol. 3, Membranes & Receptors, PG Sammes & JB Taylor, eds., Pergamon Press (1990), pp. 133-185; Ding immermans, PBMWM & PA van Zwieten, " α-Adrenoceptor . Agon 圬 ts and Antagonists ", Drugs of the Future. Vol. 9, No. 1, (January, 1984), pp. 41-55; Megens, AAHP, JE Leysen, FHL Awouters & CJE Niemegeers, " Further Validation of in vivo and in vitro Pharmacological Procedures for Assessing the α-j and a2-Selectivity of Test Compounds: (2) a-Adrenoceptor Agonists ", European Journal of Pharmacology. Vol. 129 (1986), pp. 57-64; Timmermans, PBMWM, A. de Jonge, MJMC Thoolen, B. Wilffert, H. Batink & PA van Zwieten, " Quantitative Relationships betwesn α-Adrenergic Activity and Binding Affinity of α-Adrenoceptor Agonists and Antagonists ", Journal of Medicinal Chemistry Vol. 27 (1984) pp. 495-503; van Meel; JCA, A. de Jonge, PBMWM Timmermans & PA vanZwieter, & q uot; Selectivity of Some Alpha Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Rat ", The Journal of Pharmacology and Experimental Therapeutics. Vol. 219, No. 3 (1981), pp. 760-767; Chapleo , CB, JC Doxey, PL Myers, M. Myers, CFC Smith & MR Stillings, " Effect of 1,4-Dioxanyl Substitution on the Adrenergic Activity of Some Standard a-Adreno 「eceptor Agents ", European Journal of Medicinal Chemistry Vol. 24 (1989), pp. 619-622; Chapleo, CB, RCM Butler, DC England, PL Myers, AG Roach, CFC • -4- This paper size applies to China National Standard (CNS) Μ specifications (210X2. 97 mm) A7 B7 V. Description of the invention (2)

Smith, MR Stillings & IF Tulloch, " Heteroaromatic Analogues of the α2 · Adrenoreceptor Partial Agonist Clondine ", J. Med. Chem .. Vol. 32 (1989), pp. 1627-1630; Clare, KA, MC Scrutton & NT Thompson, " Effects of α £ -Adrenoceptor Agonists and of Related Compounds on Aggregation of, and on Adenylate Cyclase Activity in, Human Platelets ", Br. J. Pharmac .. Vol. 82 (1984), pp. 467- 476; US Patent No. 5,091,528 issued on February 25, 1975 to 08.11616 »^ 2,511813? &Amp; 11110 Seoul 88. However, many compounds having the structure of the compounds of the present invention have no activity and specificity when used for the treatment of respiratory, ocular IM, or bowel diseases. What is particularly troublesome with the present invention is that-these compounds have been found to be effective nasal plugs, and often have unwanted side effects, such as high blood pressure and insomnia. There is a need for new thins that can relieve nasal congestion without these side effects. The purpose of the present invention is to provide a novel compound having prefat or nasal congestion activity. Another object of the present invention is to provide new compounds which do not cause hypotension, drowsiness, high blood pressure, insomnia or other side effects. Another object of the present invention is to provide «for the treatment of cough, chronic obstructive pulmonary disease. (C0PD) and ./Innovative compounds for air-toothing. Printed by the Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs of the Consumer Co-operative Society before filling out this page.) Another object of the present invention is to treat glaucoma and And / or a new compound of diarrhea. Yet another object of the present invention is to provide these compounds with good activity when administered orally and / or topically.太 "明 awning 逋 This paper size applies to China National Standard (CNS) A4 (210X297 mm) V. Description of the invention (3) A7 B7 The present invention is applied to compounds with plums as follows

R " R

(A) R is unsubstituted Ci-Cs alkyl or alkenyl; (b > R 'is selected from unsubstituted Ci-C3 alkyl to alkenyl; unsubstituted C2-C3 alkanosyl or alkanoyl; hydroxyl; lysozyme and oxin; and ... (c) R " selected from hydrogen; unsubstituted (^-(: 3 alkyl or alkenyl; fluorene hydroxyl; Monothio-substituted methyl groups of thiol or fluorenyl groups; unsubstituted alkyl-alkoxy groups to alkoxy groups; amine groups; unsubstituted amines; unsubstituted or Cd substituted amines; riiin; unsubstituted Unsubstituted nitros; unsubstituted nitryl group; and «(group; pharmaceutical combination containing these compounds" and prevent or treat respiratory with these compounds · 冁 · · and / or II bowel disease "A male Mingz I * The so-called "burning group" here means a straight or branched bond. * It is a saturated or unsaturated, unsubstituted or substituted. Unless otherwise stated. Alkyl or alkenyl * described above are especially alkyl; preferred «groups are" -C3 · especially C2, especially methyl; and preferred «groups are unsubstituted.-6-1 This paper is suitable for Use the Chinese National Standard (CNS) A4 specification (210X297 mm) first read the notes on the back and then fill out this page) A7 _B7___ V. Description of the invention (4) "Alkyl" here means a nicotine substitution of mirror Radical, straight or branched * unsubstituted substituted. Herein, "alkenyl" means a hydrocarbyl substituent having a bond, straight or branched, unsubstituted or substituted "as used herein "Alkino" means a substituent having a QS-structure, where Q is a hydrocarbon group. "Alkoxy" as used herein means a substituent having a Q-0- structure, where Q is a "group. "Fermented amine" means a substituent having a HH2-CO-structure *, in which one or two «氮 on the nitrogen may be substituted by a radical." Fermented amine "as used herein means a H-CO-NH- structure Substituents, where 其中 on the nitrogen may be substituted by 基. Here 谞 "halo" means ·, 獗, 涣, and _. The so-called "sub" " means a substitution with HSO-structure The radical may be substituted by «group. The so-called" sulfonamide "means a substituent having a structure of HS〇2-. Among them, 氲 may be substituted by" group. "The present invention Involves novel compounds with the following structures: ----------- Q ------ IT ------ ο, • (½ Please read the notes on the back before filling this page) Printed by Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

This paper size is applicable to China National Standards (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____B7_. V. Description of the invention (5) In the above structure * R is unsubstituted Alkyl or alkenyl groups of 1 to about 3 carbon atoms. R is preferably an alkyl group. R is more preferably a methyl group or an ethyl group, and most preferably, methyl-o. In the above structure, R ′ is an unsubstituted alkyl or alkenyl group having 1 to about 3 valence carbon atoms; there is 1 to about 3 «Unsubstituted alkylthio or alkoxy group of sulfon atom; hydroxyl group; thiol group; and halogen. R 'is preferably an alkyl group, more preferably a methyl or ethyl group, and most preferably a methyl group. Alkyl or alkoxy group R · is preferably saturated, and is preferably Cl to (: 2 is more preferably methyl or methoxy group ". It is preferably" [or Mac • More preferably, cyanide. In the above structure, R ”is selected from β; unsubstituted alkyl or alkenyl having 1 to about 3 β sulfonic atoms; methyl, thiol, or amino mono-substituted methyl Unsubstituted alkylsulfonyl or alkoxy groups having 1 to about 3 valent sulfonic atoms; amine groups; oxo; unsubstituted amidine; unsubstituted alkyl groups having 1 to about 3 sulfonic atoms Or alkenyl substituted amino group; unsubstituted arylene group; unsubstituted alkynyl group; and cyano group. R " of an alkyl or alkenyl group is unsubstituted. R "is also preferably Alkyl group is more preferably methyl or ethyl, and most preferably methyl. R "of alkyl or alkoxy is preferably condensed and is also preferably (^ or (: 2 Formyl or methoxy is a prime R "is preferably fluorine, cyano or bromine. More preferably chlorine or especially. R is an amino group " is preferably unsubstituted or methyl or ethyl Substituted. R "is also preferably cyano. Preferred compounds of the present invention are as follows Construction:

R " R

This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) I -------- ο ------ 1T ------ CT Γ Please read the precautions on the back first (Fill in this page again) Α7 Β7 V. Description of the invention (6) R and its compound ίβ Compounds: R listed in the R1 column as R '·

〆-like \ · Ν \ · Ν \ · ν \ · / \ · 7 ΗΗΗΗΗΗΗΗ CCCCCCCC 3 3 3η 3 3 ΓΓ — HHHCHHH ccccoccc H3

3 3 Η He IN H-HCOHCFC τ ', please read the notes on the back before filling out this page) The central government of the Ministry of Economic Affairs, Zhengong Consumer Cooperative, printed the compound of the present invention, which is especially useful for treatment with dysfunction, cold, nasal congestion, and others. Rhinitis M with nasal congestion and its mineral symptoms (such as rhinitis and otitis 0 are useful. At the same time, it has been found that * unwanted side effects such as hypotension, dysentery, hypertension, or insomnia can be avoided. The compound of the present invention is not limited to a specific mechanism of action. It and -2-adrenaline can be affected by tt. It is believed that other compounds related to the treatment of nasal congestion. 巳 It is found that the compound of the present invention is α-2 9 adrenal It can promote the cocoon effect on the face. It can make the turbinate meet the edge of the vascular bed. «I. It is also found that the compound of the present invention has only weak α-1 agonizing effect. * It has little or no effect on the Chinese God." The compounds of the invention can also be used for the treatment of ophthalmic diseases with an increase in the intraocular cavity. • Ningguang eyes. These compounds can be administered orally or as drops, flanks, or creamy horses for use on mammals. Sugar surface. The present invention Compounds with anti-kinetic and anti-antibiotic properties It can also be used to control Jia Yaojian's disease, such as diarrhea. -9- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 _B7_. V. Description of the invention (7) Pharmacological activity and selectivity can be determined using published test methods. The α-2 selectivity of these compounds can be determined by measuring the ability to accept waist-binding affinity. Various known α-2 and / Or a -1 can be determined by "Sister Weaving for Living" (see * For example,

(Adrenergic Receptors. L.E. Linbird, ed., Humana Press, Clifton, NJ.) The following activities are described in "The female is usually a K * tooth or other animal." The effect on the Chinese God's buried system is to take the influence of fixation on the building nerve as a sedation index. (See, for example, Spyraki, C. & H. Fibiger, " C 1 onidine-induced Sedation in Rats; Evidence for Mediation by Postsynaptic alpha-2 Andrenoreceptors ", J. Neural. Trans .. vol. 54 (1982) , pp. 153-163). Its nasal decongestion effect was estimated by nasal irritation house method. (See • For example,

Sale · »S · & E · Clejiangente," A Nev Experimental Method for Evaluating Drugs in the Nasal Cavity ", Arch. Oto I arynna. Vo 1.96 (1972), pp. 524-529) ° Its resistance The glaucoma effect is determined by measuring the intraocular pressure. (See, for example, · Printed by the Central Standard of the Ministry of Economic Affairs and Consumer Cooperatives. * Please read the precautions on the back before filling out this page.)

Potter, D., " Adrenergic Pharmacology of Aqueous Hu ^ an Dynamics ", Pharmacol. Rev. Vol. 13 (1981), PP. 133-153). Its anti-diarrheal effect is determined by the inhibition of these compounds by the forefront _-Induced diarrhea determines ◊ (see, for example, ·

Thollander, Μ., P. Hellstro · & T. Svensson, " Supression of Castor Oil-Induced Diarrhea by alpha-2 Adrenorecptor Agonists ", Aliment. -10- This paper size applies the Chinese National Standard (CNS) A4 specification ( 210X297 mm) Printed on A7 __B7 __-_ by the Central Procurement Bureau of the Ministry of Economic Affairs, Consumer Cooperatives V. Description of Invention (8)

Pharmacol. Thcrap., Vol. 5 (1991), pp. 255-262). Its anti-puffing effect is determined by the effect of this compound on tracheal contraction caused by lung stimulants such as inhaled antigens. (See * For example, Chang, JJ Husser & J. Hind, " Effects of a Hovel Leukotr i ene D «Antagonist with 5-Lipoxygenase and Cyclooxygenase Inhibitory Activity, Wy-45,911, on Leukotr i ene-D *-and Antigen -Induced Bronchoconstriction in Guinea Pig ", Int. Arch · Allergy AppI. Ibbuii .. Vol. 86 (1988), pp. 48-54 * and Delehunt, J., A. Perruchound, L. Yerger, B.. Marchette. J. Stevenson & V. Abraha ·. &Quot; The Role of Slov-Reacting Substance of Anaphylaxis in the Late Bronchial Response After Antigen Challenge in Allergic Sheep ", Am. Rev. R eso ir Pis .. Vol. 130 (1984) , pp. 748-754). Its effect on coughing is determined by the number of coughing and incubation period caused by breathing-stimulated cocoons such as inhaled citrate. (See * For example, C a 11 away, J. & R. King :, " Effects of Inhaled Alpha-2-Adrenoceptor and GABAb Receptor Agonists on Citric Acid-Induced Cough and Tidal Volune Changes in Guinea Pigs ", Eur J. Pharmacol .. Vol. 220 (1992), pp. 187-195) 0 The compound of the present invention is synthesized by the following general method: -11-The size of this paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ) (Please read the note on the back before filling this page)

, 1T .9 A7 B7

V. Description of the invention (9) OH R

1) HNO3, H2S04 2) POX3 (X = CI, Br)

X R

(Used when R is not alkyl or alkenyl) MR " (M = Na, K, Cu)

D R " R

R '12- This paper size applies to Chinese National Standard (CNS) A4 specification (2! 0X297 mm) I -------- a —----- ΐ ----- o— (please first (Please read the notes on the back of the page and fill in this page) A7 B7 1,2-Diethylamine

V. Description of the invention (10) VH >

HNV In the above scheme, when R is an alkoxy group or an alkanosyl group, the corresponding hydroxy or thiol compound is determined by the standard alkyl method (Bhatt, et al., &Quot; Cleabage of Ethers ", Synthesis 1963, pp. 249-281) K final compound derivation. In the above scheme, where r ”is an amino group, the fluorene group can be converted into a substituted methyl group or an amine by a standard conversion method. (BMarch, Advanced Organic Cheiistry, 3rd ed. Wiley, 1985) ° The following non-limiting examples provide details of synthesizing the 6- (2-oxazolinylamino group) > oxoline compounds of the present invention. 9 W Ί 5.8-Di Shenmou-6- (2-Agull 0yl »a ) Jurisdiction _ ~ »厶 $ ---------- Q ------? Τ ------ 〇_ {Please read the notes on the back before filling this page) Central Ministry of Economic Affairs Printed by the Shogunate Jeonggong Consumer Cooperative

N, HN

-NH 13 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm). Printed by ABC Consumer Cooperatives, Central Bureau of Standards of the Ministry of Economic Affairs. A7 _B7__ 5. Description of the invention (11) fi-dimethyl noisy electricity 2,5-dimethylaniline (20.73 g), glycerol (54,81 g) and arsenic pentoxide (As2〇 «» xH2〇 ) (Aldrich, 54X As, 35.06 g) · Carefully add sulfuric acid (51. 6 g) under thoron. The resulting hot solution was heated at 140-150 t: 4 hours. The reaction mixture was then cooled to room temperature and the pH was slowly adjusted to 10 by adding ammonium oxide solution (28-30X). After about 10 minutes of sickle, add ice-acid to acidify the acidic solution to pH = 5, and extract with digas methane (CHssCU) (3x500 ml). Then washed with water (2x500ml) and brine (2x500ml), dried over magnesium sulfate (MgS04), filtered, buried, evaporated, and prepared crude quinoline (31g), and then flashed on silica. Color analysis, K10X_Ethyl hexane wash the chicks. Combine the compound containing parts and evaporate them by rotary evaporation to get 5,8-dimethylttamine; 5.8-dimethyl-6-18 "!» Will be 250 5,8-Dimetholine (1.25 g) in the garden bottom burn plate is cooled to 0 X in an ice-HaCl bath under β gas; »Slowly add concentrated sulfuric acid (50 ml) in a funnel to Keep the internal temperature not exceeding 5 t: Stir the solution for a few minutes and shovel * and then cool it to -15 t in a dry ice bath with ethylene di-fermentation. Add nitric acid (1.7 ml * 69-71X) in sulfuric acid (50 «L) dropwise. ) (Using a syringe) · The rate of addition should not cause the reaction ffl degree to exceed «-31). After 10 minutes of sickle *, pour the reaction into a beaker with ice, and slowly add ammonium hydroxide solution (28-30X) to pH 10. The product was extracted with acetic acid (3x500 ml). The organic matter was dried on magnesium sulfate (MgS04), and was filtered through rotary evaporation to obtain a crude product (2.6 g). Then flash color analysis was performed on silica. M 15X ethyl acetate / hexane The young chick. _ 14 _ This paper applies Chinese National Standard (CNS) (210X2.97 mm) ---------------- 1T ------ 0— (Please first (Please read the notes on the reverse side and fill out this page) A7 B7 printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (12) Combine the parts containing the compounds and evaporate them to obtain 5,8-dimethyl -6-nitroxanthroline. Ertian Mou-6-Fang Mou It is dedicated to the dissolution of 5,8-dimethyl-6-nitro beta morpholine (1.41 g) in acetic acid (17.4 liters) * Iron (Fe > (1.21 g) and ice acid (2.56 g). This mixture was refluxed for 2 hours. The reaction was further added with Fe (1.23 g) and ice W acid (2.49 g), and refluxed for another hour. The reaction was Pour the contents into a cup with ice, add a saturated potassium sulfonate solution (28-30X) to adjust the pH to 10. Extract the product with dichloromethane • Combine the organics, dry on magnesium sulfate, filter, and turn Evaporation yielded 5,8-dimethyl-6-amino Hi-line. S Di-6-6-Hydroxyline was dated to 5,8-dimethyl-6-amino 啉 line (0.85 g) To the solution in 0.1N HC1 (52 ml) was added dropwise phosgene (0.4 ml and the reaction was stirred for 10 minutes.) At this time, a yellow sunk beach was produced. 1N sodium hydroxide (NaOH) (52 * liters) was added to the reaction. ), A white sinker was formed immediately. The reaction mixture was stirred for another 10 minutes. Then the product was extracted with diazomethane (3x100 ml). The organic calendar was evaporated to a small ft. The residue was simmered with a silica bed and 25X acid Ethane / hexane was washed away. The filter edge Hair, to obtain 5,8-dimethyl-6-isothiocyanato_line. 6- (N-2-anti-7, a) 碴 a-S.8- two-field humming on the ethyl limbs (2.00 «L) of a solution in methylbenzyl (21 ml) was added dropwise 5,8-dimethyl-6-isothiocyanoline (0.88 g) in toluene (21 ml) under argon. Solution. A white precipitate was formed during the addition process. Toluene was evaporated. The yellow-white solid was dried for 20 minutes. 6- (H-2-aminoethyl) thiomethyl-5,8-dimethylformate was obtained. Michandroline. — 15 — This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (210X297 mm) ---------- 0 ^ .-- {Please read the precautions on the back first (Fill in this page)

• ST printed by the Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumer Cooperative, A7, B7 V. Description of the invention (13) II W 龅 S. Nita even-ft- (2-Weilu Btli, a certain prevention) Pyramid 6- (1 (-2-Amine 21-based) Aceto-5,8-dimethyl0! Line (1.21 g) and _ 1, a mixture of mercuric acid (1.85 g) in ethyl acetate (41 «L) was heated to reflux When the reactant is heated to reflux, the mixture becomes brown. The reactant turns black after refluxing for a few minutes. The cold reaction mixture is filtered with diatomaceous earth. The filtrate was evaporated by evaporation, the residue was dissolved in water, and the pH was adjusted to pH 10 with a saturated potassium carbonate solution. The product was extracted with chloroform (3x250 ml). The organic was evaporated to a small amount and then silica gel was used. The bed was filtered to remove residual mercury M. The bed was filtered with denatured formazan, and the filter edge was evaporated by evaporation to obtain 1.3 g of crude product. A solution (10 ml) of the crude material in dichloromethane was used for another Silica dioxide bed "To remove the sickle material, wash the bed with 20 × saturated formazan NHΗ / gas, and then evaporate it into a crude material. Then it floats in the ethyl acetate. Hot "Chip. Filter material, namely 5,8-dimethyl-6- (2-imidazolinylamino) _line (0.51 g)" in »♦ * This cyanoline is cold in the formaldehyde HC1 was passed into the liquid to make a di-M-acid salt. The residue was evaporated by evaporation using methanol. The residue was recrystallized with acetic acid / ether. The 5,8-dimethyl-6- (2-imidazolinyl dihydrochloride was obtained. Amine > S morpho. Fenji 2 6- (2- 醯 雎 菡 菡 W Ⅲ) Synthesis of a certain table ---------- ο ----- 1, order ----- -OI. (Please read the notes on the back before filling this page)

—16 ~ This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) A 7 B7 V. Description of the invention (14) 6-¾--4.5.8-three dark Btt will be 2,5--2 Methyl-4_nitrobenzylamine (0.96 g), chlorinated hexahydrate (2.50 g), zinc gasification (0.094 g), concentrated acid (0.481 liter), and ethyl acetate (ml) The material was heated to 60t !. At this temperature, 1.3,3-trimethoxybutane (0.73 ml) was added dropwise. The reaction mixture was heated at reflux overnight and then cooled to room temperature. A 10 JK aqueous solution of sodium oxide was added, and the mixture was extracted three times with dichloromethane. The combined organics took place in sulfuric acid, and were filtered and evaporated to obtain the crude product. This crude product was purified by flash color analysis. Using 25X hexane_acid ethyl_ as cymbal. • 6-nitro-4,5,8-trimethylphospholine was obtained. 6-Amine-4.5 .8-lanff a brewed 6-nitro_4,5,8_trimethyl beta morpholine (0.60 g), dihydrate gasification seeding (IU (3.13 g > *) and acetonitrile (40 «L) The mixture was heated at 60-65 for 3 hours, and then cooled to a chamber. Add 10 × 籯 aqueous sodium oxide solution (24 liters) and water (48 ml). This mixture was extracted three times with chloroform. The combined ones were saturated with saturated Sodium carbonate is used as a solution, dried on magnesium succinate, filtered, and evaporated to obtain a crude product. This crude product is analyzed by passivation with passivation, and is prepared by washing with ethyl acetate in 25 × hexane. 6-Amino-4,5,8-trimethylquinoline. Printed by the Shellfish Consumer Cooperative of the Central Sample Bureau of the Ministry of Economic Affairs-(please read the precautions on the back before filling this page) 6- A branch of Mahita Mahjong 6_Amino_4 »5,8_trimethyl" line (0.37 g), bis-2-pyridylthiomonatofluorene carbonate (0.494 g) (DPT) (Aldrich), dimethyl A mixture of aminopyridine (0.052 g) and dichloromethane (4 ml) in a chamber «Stir for 2 hours. Add DPT 100« g • Stir with ore for 1 hour. Add DPT 100 «g and stir at room temperature for 1 hour" to evaporate the mixture _ box • Use a short column for color analysis and purification • The short column is made of sand / silica dioxide / sand calendar. * Yes-17- This paper size uses the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 _B7___ 5. Description of the invention (15) Use 20X Washing the broth with ethyl ethyl succinate in the alkane * to produce 6-isocyano-4,5,8-trimethyl "Lin. Lu 7 · A) Trishenyl under the jurisdiction of A) Yuyan A solution of amine (0.586 liters) in 2.5 ml of methylbenzyl was slowly added to a solution of 6-isothiodi-4,5,8-trimethyl HS (0.40 g) in toluene (10 ml). This reaction mixture was sown in a chamber for 2 hours, and then placed in a refrigerator overnight. The solids formed when encountering the saccharomyces cerevisiae were used. -(6- (4,5 · 8-trimethylphosphonium · linyl) urea. Ft-U-PilMtt defends against a certain trimethylquinine to prevent H- (2-aminoethyl) -fluorene ·-( 6- (4,5,8-trimethylβ-phosphonyl) sparse gland (0.461 g) · _Acid (0.602 g) * and formazan (20 «L The mixture was stirred in the room for 4 hours. The reaction mixture was filtered through diatomaceous earth and washed with diatomite M methanol. The crude product was evaporated. The crude product was analyzed and purified by flash chromatography. The formic acid solution in 20 × dichloromethane ( Containing 1 × M ammonium oxide) pupa, 6- (2-oxazolylamidoammonium) -4,5,8-trimethyl "5line was prepared. Second brew _8-(? _- 眯 醵 1 «some way and some" -4.5.8-three tops and some «periods of the Ministry of Economic Affairs of the Central Committee of the People's Republic of China and the seal of the shellfish consumer cooperative — — (please read the precautions on the back first (Fill in this page again) 8L Dissolve 6- (2-oxazolamine: ylamino) -4,5,8-trimethylpyroline (0.406 g) in concentrated hydrochloric acid (0.813 «L) in formazan (4 Ml). To this solution was added ether (7 ml). This solution was allowed to stand at room temperature for 3 days. The crystals formed by the saccharine were prepared with fermented saccharine to obtain 6- (2-imidazolyl-aminoamino group 4,5,8-trimethyl "hydrazone monohydrate. Fen Confession 3 R.8-Ertian is very indifferent to defeating Lu Qi)-4-Shen Xun is suspected to be a party ^; 18 ~ _ This paper size applies to China National Standards (CNS) A4 specifications (210X297 (Mm) V. Description of invention (16 A7 B7

V HN

-NH Printed by S. 8-dimethyl-1-6-88-4-4-g for 5.8-dimethyl-4-oxolinone (5.18 g · 29.9 奄Moore) (prepared according to the method of Burcfcha 1 ter, et al., J. A. Che. Soc. Vol. 70 (1948), p. 1363) 30 liters of sulfuric acid was placed in a flask. After stirring for 10 minutes, the coriander bottle was cooled in ice, and concentrated nitric acid (1.90 «liter, '30 .2« mol) was added dropwise. After the addition was complete, the mixture was stirred in ice for 15 minutes. The mixture was poured onto crushed ice and allowed to warm to room temperature. Filtered gray solids • Wash with water. The solid methyl formase was reconstituted to obtain 5,8-dimethyl-6-nitro-4- «line_. i- 虿 -S. 8- 二 申 某 -fi- «其 -4- 讅 酽 将 5,8-dimethyl-6- 礴 基 -4-ΗίΗ 酽 (3.01 g · 13.8 mmol) and Phosphorus trioxide (41.3 g, 268 mmol) was placed in a supply bottle. The mixture was refluxed for 3 hours under agitation while stirring. After cooling to room temperature, the mixture was poured onto crushed ice. * Concentrated argon ammonium (100 ml) was added. Extraction with gas-form (2x200 ml) and drying on potassium mineral acid * I & bur, evaporation and removal of solvent to obtain 4-chloro-5,8-dimethyl-6-fluorenyl-4-β-line Alas. 5.8-Di_some-4-methylargon-6-pemium__ will be 4-gas_5, δ_dimethyl-6-nitro-4-¾olinone (U52g · 5U «Mo Er) Place sodium trimethoxide (2.2 7 g · 4.2 mmol) and formazan (25 5 liters) in a tin bottle. 19 This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back first and then fill out this page) The Central Standards Bureau of the Ministry of Economic Affairs printed only A7 _B7 __5 7. Description of the invention (17) The mixture is refluxed under tritium for 21 hours, stirring occasionally, washed with water (100 liters) and formazan (50 ml), and extracted with two «methane (2x200 ml). The organic layer was dried over potassium mineral acid, filtered and evaporated. Product M flash color Eaves analysis (7/3 hexane / acetic acid) · 5,8-dimethyl-4-methoxy-6-fluorenyl_line was obtained. Α-Κ 某 -5.8- 二 印 某 -4- 申 Hydrogen "For the supply of 5,8-dimethyl-4-methoxy-6-nitro (1.16 g * 5.0 亳 ear) and dihydrate" Huayao (5.64 g, 25 «its ears) and ethyl yeast (50« liters) are placed in a tin bottle. The mixture was decanted for 1 hour, diluted with water (100 ml) and ammonium hydroxide (30 liters), and extracted with chloroform (2 x 200 liters). The organic part was dried on potassium phosphate, and then evaporated and evaporated to remove the solvent. 4-Amino-5,8-dimethyl-4-methoxyβ! Line was obtained. SS-Dig, its -fi-value, "Zhong Mou" 6-Amino-5,8-dimethyl-4-methoxy beta Fluoroline (987 mg, 4.9 millimoles) * Di-2 -A solution of pyridylthiocarbonylarsinic acid (1.74 g · 7.5 mmol) and dichloromethane (70 ml) was stirred at room temperature for 2 hours. The solvent was removed by burial evaporation, and the product was purified by flash color analysis (8/2 hexane / acetic acid) to obtain 5,8-dimethyl-6-isothiocyanato-4-methoxyβ. Morpho. 5.8-Di-S-4, 4-Argon-A, Anti-7, 篇) Aiming at the article) 晔 瞅 Ethyldiamine (2.25 g * 37 mmol), dropwise addition of 5,8-dimethyl-6 -A solution of isocyano-4-methoxybetaline (501 mg, 2.1 mmol) in dichloromethane (20 ml). This mixture was stirred at room temperature overnight. In case of «formation of solids«, use less "II" methane washing. Residual solid "5,8-dimethyl-4-methoxy-6-(-Η- (2-amine ethylenediamine is prepared after several hours of drying in a vacuum, please read the precautions on the back before filling this page ) -20- This paper size applies to China National Standards (CNS) Α4 (210 X 297 mm) Printed by the Industrial and Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs Α7 Β7 V. Description of the invention (18) *) «[昊 基) Eyeline. ^ Difluorenyl-4-sulphonyl-6- (2-taste_even-yl), 1 «will be 5,8-dimethyl_4-methoxy-6-(-11- (2-amine ethyl Base) succinyl base) "morpholine (493« g · I.δ ml) and acid acid (537 mg, 1.7 mils >) in a formazan mixture was stirred in the chamber for 2 hours * and then fermented with silicon Filter. Add the lysate to 10X potassium carbonate solution (100 liters), and extract with chloroform (3x200 ml). Organic mash is dried on sulfonic acid. Tritium analysis (9/1 aeroform / M-amino hydrazine and methylformaldehyde), and 5,8-dimethyl-4-methoxy-6- (2-oxazolinylamino) was obtained. Formazan / HCL within 12N is converted into dihydrazone dihydrate hemihydrate. 啻 基 4 • 4-value is very -5.8- 二 珥 某 · β · (2 · 眯 雎 at 某 路 某) 1 § Ming will

4-^-5.8-dimethyl-fi-BS, g.att will be 5,8-dimethyl-6_nitro-4-β morpholine (7.12 g, 32.7 «mole), phosphorus aoxane (7.47 G · 26.12 mmol) * pyridine (5.3 ml) and toluene (90 ml) were heated at 90 × 3 for 6 hours. Filter this mixture while it is still hot, and wash it with water and dichloromethane. Extraction of IS material with digas methane (3x100 奄 l) -21- This paper size uses Chinese National Standard (CNS) A4 specification (210X297mm). Q ------ 1Τ ------ 〇Ι (Please read the precautions on the back first and then fill out this page.) A7 _B7___ printed by the Ministry of Economic Affairs, Central Bureau of Work and Consumer Cooperatives. 5. Description of the invention (19), the combined organic calendar is dried (acid acid), evaporated, 4-Bromo-5,8-dimethyl-6-nitro-line was obtained. 4-1 [A-S.8-dimethyl-a-fi- «A certain" Aiming 4-cyano_5,8-dimethyl-6- (2-imidazolinylamino) "Porphyrin (3.87 g , 13.77 millimoles), a mixture of nidus (3.67 g, 41.31 millimoles) and dimethylmethosamine (70 ml) stirred at room temperature for 30 minutes • then heated to 155 t: and here Stir for 1 hour. Water was added and the reaction mixture was filtered. Water for sedimentation and dichloromethane. The extract was extracted with dichloromethane (3x125 «liter). The combined organic extracts (sodium sulfate) were evaporated and evaporated.纆 Small column for color analysis and purification • The short column is composed of sand / W silica / sand • Wash with 氱 imitation * _ to obtain 4-cyano-5,8-dimethyl-6-nitroline . 6-Lumou-4-Almost 4-Cyano_5,8-dimethyl-6-nitroenaline (2.54 g, 11.2 mmol) · Aqueous stannous dihydrate (12.6 g, 55.9 A mixture of millimolar) and acetic acid (200 ml) was heated at 60 " C for 1.5 hours. The reaction was cooled to room temperature • Water (60 liters) was added. This compound was extracted with 10XS oxidized »aqueous solution (70 ml) _ (chemically) and extracted with di« methane (3x150 ml). Drying (sodium sulfate) and evaporation * to obtain 6-amino-4 -gas-5 , 8-dimethyl is called. 4- «yl-5.8-dimethyl-6-cyanocyanine" _ 6-amino-4 · cyano-5,8-dimethyl "line (2.0 G, 10.15 millimoles), di_2-pyridylthiocarbonylphosphonium carbonate (2.52 grams, 10.86 millimoles), dimethylaminopyridine (0.266 grams, 2.18¾ mole) and digas methane (62 · L) Stir the mixture at room temperature for 1.5 hours. Evaporate and analyze the residue with a short column for coloration. • The short column is made of sand / silica dioxide / sand. Standards are applicable to Chinese National Standard (CNS) A4 specifications (21 (ϋ < 297 mm) (please read the notes on the back before filling out this page), ΤΓ 1. c A7 B7 ____; _ V. Description of the invention (20) Methane is used as a sickle agent to produce 4-thiyl-5,8-dimethyl-6-isothiocyanoβ-line 〇6- [11-2-amineethyl (Something) 碴 艳 某 -14- 澶 even -1-Ertian Luo «[_ Yu Shen Ethyl Diamine (2.93 ml) To a solution in methylbenzyl (30 ml) was added a solution of 4-cyano-5,8-dimethyl-6-isocyanatocyanoline (2.1 g, 8.78 * mol) in toluene (100 ml). The reaction mixture was stirred at room temperature overnight. «A solid solution was formed, washed with a toluene-like bottom, and dried to obtain 6-(» (-2-aminoethyl) thiomethyl-4-cyano-5 , 8-dimethylphospholine. 4-Cyano-S.8 · dimethyl-6-(? .- «Protection is very safe) 6- (N-2-aminoethyl) thiomethyl A mixture of -4-cyano-5,8-dimethyl "line (2.49 g, 8.32 mmol), _mercury acid (2.81 g, 8.82« Mole) and formazan (100 ml) in the room group 攫Stir for 2 hours * to form a black suspension. This suspension is filtered on a two-atomized silica gel bed and a thin layer of silica, and the bed is rinsed with a carbamate. The substance is evaporated to dryness. A short column is used for color analysis and purification. The short column is composed of sand / W silicon dioxide / sand. • Di ((methane / formaldehyde / ammonium hydroxide U5M5 / 2) is used as a washing agent. 4-cyano-5,8-dimethyl-6 is prepared. -(2-imidazolinyl limbyl group) tt morpholine (partially fermented acid). This «Ming is another sister compound, this sister compound contains a safe and effective amount of the« Ming compound » Or a pharmaceutically acceptable salt thereof "and an acceptable load on a gull." The safe and reasonable amount "here means in a correct medical practice. The amount of the compound of the present invention is sufficient to wait for treatment. Positive improvement in the disease's occurrence ** But its level is so low as not to cause severe side effects (ie reasonable benefit / hazard ratio). The safety of the compound of the present invention may depend on the age of the patient to be treated (please read the note on the back first) Please fill in this page again for matters) -23- This paper size adopts Chinese National Standard (CNS) A4 specification (210X297 mm) Printed by the Ministry of Economic Affairs, Central Bureau of Standards and Commerce of the People ’s Republic of China Duo A7 Β7 V. Description of Invention (21) and Alligator conditions, the severity of the disease, the length of the treatment period, the sexual properties treated with K at the same time, and the acceptable carrier used in a particular medical treatment, etc., vary according to the expertise of K. The sister compound of the present invention preferably contains the compound of the present invention with a weight-to-ft ratio of about 0.0001X to about 99X, more preferably about 0.01X to about 90X; and preferably about 10X to about 50X, and preferably about 5X to about 10X. And preferably about IX to about 5X, and preferably about 0.1 to about U. In addition to the compounds of the present invention, the sister compounds of the present invention may contain an acceptable amount on the surface. The "acceptable" term here means one or more compatible solid or liquid filled with diluents or encapsulated substances. Some of these are intended to be administered to humans or lower animals. The so-called " compatible fishing " here means that the components in the compound can be mixed with the compound of the present invention, and can also be mixed with each other. * Under normal use, no interaction will occur and the effect of the compound will be caused. Naturally, the acceptable load must be high-grade and low-toxic in nature, suitable for human or lower animals to be treated. Used as a pharmaceutically acceptable load Examples of agent substances or their ingredients include sugars, such as lactose, sucrose, and glucose; starches, such as corn splash powder and potato starch: hunastatin and its derivatives • such as carboxymethyl cellulose, sodium • ethyl cellulose * And methylcellulose; powdery scutellaria glutinosa; malt; gelatin; talcum powder; solids and confusion * such as stearic acid and magnesium stearate; calcium carbonate; vegetable oils such as peanut oil, nanzi oil · Sesame oil • 撖 «Oil * corn oil and cocoa butter; multiple yeasts, such as acrylonitrile • glycerol • sorbus • mannan, and polyethylene dienzyme: thin acid; emulsifiers, such as various spit irrigation; Agent, such as laurel base -24- This paper size applies to China National Standards (CNS & g t; Α4 specification (210X297 mm): C ------ ίτ ------ Q-(Please read the precautions on the back before filling this page) A7 -_ ^ _ B7__ V. Description of the invention ( 22) Sodium acid; Coloring and flavouring soaring and stable noodles; Antioxidant tincture; Preservative cocoons; Pyrogen-free water: Isotonic saline; and Phosphate soothing itch solution. Medically acceptable in combination with the compound of the present invention The selection of si is basically dependent on the route of administration of the compound. If the compound is intended for injection, the preferred medically acceptable is sterilized physiological saline, and blood-compatible suspension blue, Its pH has been adjusted to about 7.4. Printed by the Consumer Cooperatives of the Central Bureau of Quasi-Economic Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). The preferred way of administering the compounds of the present invention is by oral administration. The preferred unit shape of K is tablet cocoon • capsules • lozenges, chewable tablets • etc. Such unit cocoons contain a safe and effective amount of a compound of the present invention, preferably about 0.01 «g to about 200 mg • More preferably about 0.1 mg to about 50 mg • More preferably about 0.5 «gram to 25 mg • Still preferably about 1 mg to about 10 «g. Should be used in the oral administration of beta-acceptable β-medicine acceptable unit" is known by this technology B. Tablets-Generally containing Fu II II pharmacologically compatible saccharine as eaves dilution Noodles • such as calcium sulfonate * sodium sulfonate, glutamate 31 • lactose and cellulose; combined with orchids such as instant powder • gelatin and sucrose; disintegrates such as rice flour, alginic acid and croscai ^ elose; Magnesium citrate • Stearic acid and talcum powder. «Migrating agents such as silica can be used to improve the flowability of powdery mixtures. Color-enhancing surfaces can be added • Such as FD & C dyes M piled into melons. For example, aspartaie, saccharin, mint leaven * mint, and fruit-flavored noodles are useful ingredients. Capsules typically contain one or more of the aforementioned solid dilutions. The selection of ingredients is dependent on taste, cost, stability, etc. The second test "• is not an important purpose of the present invention, and those skilled in this technology will also easily decide. 1 2 5 — This paper size applies to China National Standards (CNS) A4 specifications (210X297 mm) Printed by the Central Labor Bureau of the Ministry of Economic Affairs and Consumer Cooperatives A7 _B7__ 5. Description of the invention (23) 纆 口 姐 合 君 遢 includes Liquid surface solution, emulsion • 騄 float liquid and so on. The pharmaceutically acceptable Zanlan which is used in making these sister compounds is well known in this art. These liquid chelate compounds preferably contain the compound of the present invention from about 0.001 X to about 5X, and more preferably from about 0.01 »to about 0.51 _ pulp, __, emulsion, and suspension. The general ingredients include acetic acid. Glycerin * acrylic fermentation, polyethylene dienzyme, liquid fermentation, sugar, sorbose and water. Common suspension blues used in suspensions include methylcellulose ·) »Vitamin Carboxymethyl Sodium, Avical® RC-591 · tragacanth gum and alginic acid"; typical moisturizing agents include "capsules and polyethyl acetate" Ethyl ether; typical preservatives include paraben and sodium benzoate.口 Mouth 钃 钃 合物 can also contain one or more ingredients such as sweet miso, flavoring and color enhancement. Other compositions for achieving systemic delivery of the compounds of this invention include sublingual and elixirs. These compounds usually contain one or more soluble filling materials such as sucrose, sorbose and glucosamine; and combined orchids such as acacia, microcrusted cellulose, carboxymethyl cellulose, and hydroxymethyl cellulose. Propyl methylcellulose. It can also include the above-mentioned shifting orchids • 潸 lan cocoons * sweet taste rain • color enhancement _ • antioxidants • and flavor cocoons. A preferred form for administering the compounds of the present invention is topical application at the site of this activity; intranasal cocoons used in nasal congestion • inhalation langes used for air sputum, eye cocoons, coagulants and creams for eye diseases纆 口 雨 for lumbosacral disease. The comparative compounds of the present invention include an aqueous solution for topical intranasal administration containing a safe and effective amount of a compound of the present invention. Such sister compounds preferably contain from about 0.00U to about 5X of the compound of the invention, and more preferably from about 0.01X to about 0.5X. This kind of sister He-26- this paper; 1 degree applies Chinese national standard ((: 1 ^;) 8-4 specifications (210/297 mm) • Q II-(Please read the notes on the back before filling out this page ), 5T

1. ./IV A7 B7__ V. Description of the invention (24) The substance generally also contains a safe and effective amount of preservatives, such as benzyl chloride and ethyl mercury dipped in sodium salicylate; Acid salts; isotonic A such as sodium carbonate; antioxidants such as ascorbic acid; aromatic noodles; and acids that adjust the pH required for these aqueous compounds with M. Preferred compounds of the present invention include aqueous solutions, suspensions and dry powders, containing safe and effective amounts of the compounds of the present invention for nebulization and topical inhalation administration. Such sister compounds preferably contain the compounds of the present invention from about 0.1X to about 50X, and more preferably from about IX to about 20X. These sister compounds are usually contained in a container with an atomizing device. Such sister compounds generally also contain cocoons • such as chlorosulfonic compounds 12/11 and 12/114; cocoons such as water, glycerol, and acetic acid; stable and stable * such as ascorbic acid, sodium pyrogenate; antiseptic_ · Such as chlorinated pyridylpyridine and helium benzoic acid; isotonic tinctures such as sodium carbonate; M and seasonings such as saccharin sodium; central sample of the Ministry of Economic Affairs must be printed by the Shellfish Consumer Cooperative-(Please First read the notes on the reverse side and then fill out this page.) Preferred compounds of the present invention include an aqueous solution * containing a safe and effective amount of a compound of the present invention for topical administration. Such sister compounds preferably contain compounds of the present invention at about (K 0001X to about 5X, more preferably about 0.01X to about 0.5X. Such sister compounds generally also contain one or more preservatives, cobyl chloride * Ethylmercury sodium thiosalicylate, benzylmercury gallate; 谓 -shaped term • such as poloxamers, modified cellulose • polyethylene /% slightly _ and purified water ί and other strong • such as sodium Glycerol and glycerol; retarding agents such as _acids, saccharates, phosphates, and boric acid; and the acids and »required for the preparation of these formulations with MG. The present invention is preferred Materials include solids, such as tablets and capsules, and liquids such as solutions, suspensions, and emulsions (preferably contained in chopped capsules), which contain safety-27- This paper is scaled + National Standard (CNS) A4 specifications ( 210X297 mm) A7 B7 V. Description of the invention (25) An effective amount of the compound of the present invention, κ, is administered orally to the lumbo-sacral tract for topical use. Such sister compounds preferably contain about 0.01 mg to about 100 «gben Inventive compound • More preferably about 0.1 «g to about 5 g. This kind of sister compound can be applied by conventional methods. Generally it is changed by pH or time. The coating · M releases the compound of the present invention in the vicinity of the local application required in the lumbar tract, or at the same time does not extend the effect of M. Such a shape generally contains, but is not limited to, o-benzyl dicarboxylic acid fiber O-benzyl dicarboxylate polyethylene_acid_, o-benzyl dicarboxylate hydroxypropylmethyl 钃 vin, ethyl 素 vitamin * Eudrag it »coatings 钃 紫 and purple error tablets. 5 workers of the Central Bureau of the Ministry of Economic Affairs Consumption Cooperative Seal-(Please read the notes on the reverse side and fill in this note) The sister compound of the present invention may contain other artifacts as required. Non-limiting examples of other artifacts used in the sister compound of the present invention and its _Amount • Includes: drugs used in the respiratory system: orthodox antihistamines, such as clotampiramine • about 1 «g to about 4 g per lang, diphenhydramine, british ft about 10« g to about 50 Milligrams; non-sedative anti-anaesthesia amines, such as terfenadine · about 30 mg to about 60 mg per ft of loratadine, about 5 mg to about 10 ¾ g per gram · and cetirizine, about 5 mg to about 10 per dose Mg; expectorants, such as • guaifenesin > about 100 mg to about 200 mg per two; cough suppressants, eg • Right armour South • about 5 mg to about 30 mg per cocoon; and analgesics, such as ibuprofen, about 100 mg to about 800 milligrams per cocoon 11 • and _aminophenol • 毎 _ about 80 «g To about 1000 milligrams; ophthalmic drugs; ethmidine _ _ _ inhibits cocoons, for example, echothiophate • topical tincture contains about 0.03); to about 0.25X; and lumbosacral; antidiarrheal cocoons, for example, loperaiide, Each amount is about 0.1 mg to about 1.0 mg, and the amount of bismuth soaked in water is about 25 mg to about 300 g. -28-This paper size is applicable to China National Standard (CNS) Λ4 specification (210X297 mm) ) Α7 Β7 Printed by the Central Laboratories of the Ministry of Economic Affairs and Consumer Cooperatives V. Description of the invention (26) In another aspect of the present invention, a safe and effective amount of the compound of the present invention is given to people who have or will suffer from nasal congestion. Methods of treating or preventing nasal congestion in animals. This kind of nasal congestion may be accompanied by other diseases in humans. These diseases include, but are not limited to, seasonal allergic rhinitis, acute upper respiratory virus infection, rhinitis, year-round rhinitis, and vasomotor rhinitis. The compound of the present invention is administered within a range of about 0.001 mg / kg to about 10 mg / kg *, more preferably about 0.01 mg / kg to about 5 mg / kg, and most preferably about 0.1 mg / kg to About 1 mg / kg. This amount is preferably given orally. According to the present invention, the frequency of administering the compound of the present invention is preferably about 1 to 6 times / day, more preferably about 2 to about 4 times per day. This frequency and frequency are also suitable for treating other respiratory diseases such as otitis media, cough, COPD and discouragement. Another aspect of the invention relates to a method of treating or preventing glaucoma by administering a safe and effective amount of a compound of the invention to a human or lower animal suffering from or suffering from glaucoma. The amount of Λ administered by the present compound is within the range of about 0.01 micrograms / kg to about 10 mg / kg. More preferably, it is about 0.001 mg / kg to about 1 * g / kg, and most preferably about 0.01 g / kg. To about 0.1 kg, kg. This amount is preferably given intramuscularly. According to the present invention, the frequency of administering the compound of the present invention is preferably about 1 to δ times / day. More preferably, it is about 2 to about 4 times per day. Another aspect of the present invention relates to a method of administering a compound of the present invention to humans or lower animals suffering from diarrhea or suffering from diarrhea to treat or prevent functional rickets * such as abdominal ulcers. The cocoon given by the compound of the present invention at one time 29- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) —--------- QI ----- ίτ —---- -ο, '(Please read the precautions on the reverse side before filling out this page) Printed by A7 B7, Work Cooperative Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (27) The maximum is about 0.001 mg / kg to about 10 mg / Kg_, within the range of about 0.01 mg / kg to about 5 g / kg, more preferably about 0.1 mg / kg to about 1 mg / kg. This dose is preferably administered orally. According to the present invention, the frequency of administering the compound of the present invention is preferably about 1 to 6 times / day, more preferably about 2 to about 4 times per day. The following non-limiting examples illustrate sister compounds and methods of use. Example 4 □ _ 铨 _ Μ will be injured / »f Taiwan Jing) Compound 2 20.0 Microcrystalline cellulose (Avicel PF 102β) 80.0 Dicalcium phosphate 96.0 Pyrolytic silica (Cab-0-Si 1« ») 1.0 Magnesium Stearate 3.0 Sickle 200.0 Patients with nasal congestion take one capsule. The ft plug disappeared. Fenxiong 5 Cocoon i amount per milligram (mg) Compound of the present invention 1 15. Glycan SI glycolysis 255.6 Microcrystalline Avicel PH 101st 100.8 Di-Pac® 199.5-30 One paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) ---------------- tT ------ 9 * (Please close the back first Please note this page before filling in this page) · A7 B7 V. Description of invention (28) Artificial orange miso succinate sodium stearate magnesium stearate FD & C yellow 6 «Dye pyrolytic silica (Cab-0-Sil® ») Total 15.0 3.0 3.0 2.7 600.0 Patients with nasal congestion swallow one capsule. The nasal congestion actually subsided. * MR soldiers glan ffl meeting the amount of ingredients / 铨 wrapped Beijing compound of the present invention 7 glyceroglycoside microcrystalline cellulose (Avicel Ρ101 101 mint miso essence total 2.00 2.00 29.00 0 .. 25 0.08 33.33 I QII ( (Please read the notes on the back before filling out this page)

• 1T Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Place a patch under the tongue of a patient with nasal congestion and let it dissolve. The nasal congestion disappeared quickly. -31 This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) A7 B7 V. Invention description (29) Fen "7 Emperor Yuhua IH will ft! Crucible ug summer / ¾ an central sample of the Ministry of Economic Affairs Benbei Consumer Co., Ltd. printed the compound 3 of this invention 0.20 Gasified benzyl 0.02 Ethylmercury Thiohydrate Sodium 0.002 d-Sorbic glycolysis 5.00 Glycine 0.35 Aromatic 0.075 Passivated water_ * Total 100.00 for patients Patients with nasal congestion are relieved with «Aerosol Per Nostril«. Window Li 8 won the A-chip IH meeting _ 1/10 Nasal congestion composition * / compound of the present invention 4 0.10 Benzoyl chloride 0.02 Ethylmercury sodium thioate 0.002 Hydroxypropyl methylcellulose (Metolose 65SH4000®) 1.00 Aromatic sodium 0.06 (0.65 X) Fistula and sickle meter 100.00 --------- (Please read the notes on the back of the two readings before filling out this page) Order -〇Ί. -32- This paper size applies to China National Standard (CNS) A4 (210X297 mm) A7 B7 389764 V. Description of the invention (30) Use a dropper to infuse 1/5 liters of this composition into each nostril of a patient with a ft plug. The nasal congestion is substantially relieved. Fen IO · Β λ 醻 霪 会 物 成分 (Xg // 兹)) The compound of the present invention 6 5.0 alcohol 33.0 ascorbic acid brewing 0.1 peppermint yeast 0.1 耱 refined sodium 0.2 advance rain (F12, P114) 100.00 Patients with asthma use a cocoon meter inhaler to inhale the second-sponsor compound. The chewing situation is effectively relieved. «« 10. (Please close the precautions on the reverse side before filling out this page) Printed by the Central Laboratories Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, to produce the compound 1 of the present invention. Sodium pyrohydroarsonate (0.9X) Total Tengpu "Science and Technology" (X 竃 昙 / Town) 0.10 0.01 0.05 0.50 0.10 _ Μ 100.00 33- This paper size applies to Chinese National Standards (CNS) Α4 size (210 × 297 mm) 89r / (389764 A7 B7 V. Description of the invention (31) 1/10 liters of this sister compound is directly given to Ning Guang "Patient internal pressure of each eye plate subsides substantially" Example 1 1 Printed Compound 5 of the Invention Compound 5 Benzoic acid chlorpheniramine acetic acid (95X) formazan eucalyptus oil taste _ sucrose carboxymethyl cellulose (CMC) Crystalline Visso and CMC Sodium (Avicel RC Polysorbate 80 Glycerol Sodium Fermentation FD & C Red No. 40 Dye 耱 Jing Na 犟 Sodium Phosphate Monohydrate Betulinic Acid Sodium Birch Birch Calcium / 1 S Side by side 15 «g 4 mg 1.8 g 1.5 ml 12.5 g 7.55« g 0.05 ml 7.65 g 7.5 mg 591®) 1δ 7.5 mg 3.0 mg 300 «% 300 g 3 g 22.5 mg 44« 28 mg __ 15 ml --------- Q — I (Please read the precautions on the back first Please fill in this page again), tr This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) Printed by the Shell Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 58S764 V. Description of the invention (32) To make nasal congestion and susceptibility Patients with runny nose brew 15 liters of sputum by volume> nasal congestion and runny nose are effective to relieve. Fen example 12 □ • Mochi Crude Club »1 ingredient contains 昙 / 15 units and _ compound of the invention 8 30 mg sucrose 8.16 g glycerin 300 mg sorbitol 300 mg parabens 19.5 g g parabens 4.5 mg peppermint 22.5 «g eucalyptus oil 7.5 mg flavour two 0.07 ml FD & C red 40 dye 3.0 mg A total of 15 milliliters of 30 milligrams of hydration water makes the patients with nasal congestion 15 ml of alcohol free in the mouth and abdomen. 鼻 The nasal congestion disappears substantially. Although 巳 describes the specific embodiment of the present invention, those skilled in the art will understand that the present invention also Various changes and modifications can be made The spirit garden of the present invention is still not carved. The attached patent application scope includes all the changes in the garden of this invention. This paper size is applicable to the Chinese family standard (CNS) A4 specification (210X297 mm) 4 (Please read the 4 on the back (Please fill in this page again for attention) 4

Claims (1)

Patent No. 84102759 was filed by the applicant 389764 Chinese patent application 0g revised 7 £ (November 8β) Α8 BS C8 D8 VI. Application scope of patent amendments to a structural compound as follows: Standard for printed wood paper: China National Standard (CNS) A4 (210X297mm) --------------- ir ------ final ----- ^ -------.................. (please note the f item first, and then the t page). Where (a) R is an unsubstituted alkyl or alkenyl group R having 1 to 3 pseudo carbon atoms, and R is a group; (c) R ”is an alkenyl group 1 to; To 3 carbon atoms and halogens. The root application is selected from the group of pseudo carbon atoms with 3 to 3 carbon atoms that have 1 to hydroxyl groups; Take 1 to 3 㑩 3 carboenzyme groups; and 1 to 3; untaken enzymes; unsubstituted glycosamino groups; and unsubstituted alkane carbon atoms of cyano item 1 Halogen; Carbon or amine-substituted alkane or fluorenyl group; halo group. Compound substituted by alkyl or alkene unsubstituted substituted alkene and unsubstituted thio-substituted thio or alkene have 1 to 3 elements; Wherein R "group or alkenyloxy group; cyano's or alkenyl group or alkoxy alkyl or methyl group; having an oxygen group; a substituted group of an alkyl group; ; A compound having 1 to a group; an amine group; the second item of the patent plaque, wherein R is a Shen group and the patent No. 84102759 is filed by the applicant 389764 Chinese Please apply for a patent of 0g for 7 £ (November 8β) Α8 BS C8 D8 6. The scope of the patent application is to amend and supplement the following structural compounds η The Central Samples Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives, printed wood and paper scales, using the Chinese national ladder Standard (CNS) A4 specification (210X297 mm) --------------- ir ------ final ----- ^ -------... ............ (please note the f item first, then t page). Where (a) R is an unsubstituted alkyl or alkenyl group R having 1 to 3 pseudo carbon atoms, and R is a group; (c) R ”is an alkenyl group 1 to; To 3 carbon atoms and halogens. The root application is selected from the group of pseudo carbon atoms with 3 to 3 carbon atoms that have 1 to hydroxyl groups; Take 1 to 3 㑩 3 carboenzyme groups; and 1 to 3; untaken enzymes; unsubstituted glycosamino groups; and unsubstituted alkane carbon atoms of cyano item 1 Halogen; Carbon or amine-substituted alkane or fluorenyl group; halo group. Compound substituted by alkyl or alkene unsubstituted substituted alkene and unsubstituted thio-substituted thio or alkene have 1 to 3 elements; Wherein R "group or alkenyloxy group; cyano's or alkenyl group or alkoxy alkyl or methyl group; having an oxygen group; a substituted group of an alkyl group; ;; A compound with 1 to base; amine group; Patent No. 2 in the patent plaque, where R is Shen Ji and the central government bureau of the Ministry of Economic Affairs, male workers' consumer cooperative Means A8389764?! D8 six, patented range R 'is a hydrocarbyl moiety of any group. 4. The compound according to item 2 of the scope of patent application, wherein R is methyl and R 'is selected from methyl, ethyl, methoxy, chlorine and bromine. 5. The compound in the scope of patent application of Genbo, in which any hydrocarbyl part of R " is unsubstituted. * 6. The compound according to item 4 of the scope of patent application, wherein R " is selected from the group consisting of argon, methyl, ethyl, methoxy, cyano, gas and fluorine. 7. The compound according to item 3 of the application, wherein R is methyl. 8. The compound according to item 6 of the application, wherein R is methyl. 9. The compound according to claim 5 in which R and R 'are both methyl. 10. According to the patent claim 3, R is methyl or ethyl, and R " is hydrogen. Π · 榑 撺 The compound in the patent application No. 8 wherein R " is selected from hydrogen, cyano and oxygen. 1 2. A patent pending for examination. A compound in the scope of item 9, wherein R "is hydrogen. 13.-A peony composition having 0-2 adrenergic receptor antagonistic activity, which contains ... (a) A safe and effective amount of a compound according to any one of the scope of application 1, 5 or 8 and (b) an acceptable carrier on peony. --------- ^ ----- -1T ------ line (please read the precautions on the back before t this page) The paper size of the table is applicable to China National Standard (CNS) A4 specification (2 丨 0 > < 297 mm)